B cell surface markers have been generally suggested as targets for the treatment of B cell disorders or diseases, autoimmune disease, and transplantation rejection. Examples of B cell surface markers include CD10, CD19, CD20, CD21, CD22, CD23, CD24, CD37, CD53, CD72, CD74, CD75, CD77, CD79a, CD79b, CD80, CD81, CD82, CD83, CD84, CD85, and CD86 leukocyte surface markers. Antibodies that specifically bind certain of these markers have been developed, and some have been tested for the treatment of diseases and disorders.
For example, chimeric or radiolabeled monoclonal antibody (mAb)-based therapies directed against the CD20 cell surface molecule specific for mature B cells and their malignant counterparts have been shown to be an effective in vivo treatment for non-Hodgkin's lymphoma (Tedder et al, Immunol. Today 15:450-454 (1994); Press et al, Hematology, 221-240 (2001); Kaminski et al, N. Engl. J. Med., 329:459-465 (1993); Weiner, Semin. Oncol, 26:43-51 (1999); Onrust et al, Drugs, 58:79-88 (1999); McLaughlin et al, Oncology, 12:1763-1769 (1998); Reff et al, Blood, 83:435-445 (1994); Maloney et al, Blood, 90:2188-2195 (1997); Maloney et al, J. Clin. Oncol, 15:3266-3274 (1997); Anderson et al, Biochem. Soc. Transac, 25:705-708 (1997)). Anti-CD20 monoclonal antibody therapy has also been found to ameliorate the manifestations of rheumatoid arthritis, systemic lupus erythematosus, idiopathic thrombocytopenic purpura and hemolytic anemia, as well as other immune-mediated diseases (Silverman et al, Arthritis Rheum., 48:1484-1492 (2002); Edwards et al, Rheumatology, 40:1-7 (2001); De Vita et al, Arthritis Rheumatism, 46:2029-2033 (2002); Leandro et al, Ann. Rheum. Dis., 61:883-888 (2002); Leandro et al, Arthritis Rheum., 46:2673-2677 (2001)). The anti-CD22 monoclonal antibody LL-2 was shown to be effective in treating aggressive and relapsed lymphoma patients undergoing chemotherapeutic treatment (Goldenberg U.S. Pat. Nos. 6,134,982 and 6,306,393). The anti-CD20 (IgG1) antibody, RITUXAN™, has successfully been used in the treatment of certain diseases such as adult immune thrombocytopenic purpura, rheumatoid arthritis, and autoimmune hemolytic anemia (Cured et al, WO 00/67796). Despite the effectiveness of this therapy, most acute lymphoblastic leukemias (ALL) and many other B cell malignancies either do not express CD20, express CD20 at low levels, or have lost CD20 expression following CD20 immunotherapy (Smith et al, Oncogene, 22:7359-7368 (2003)). Moreover, the expression of CD20 is not predictive of response to anti-CD20 therapy as only half of non-Hodgkin's lymphoma patients respond to CD20-directed immunotherapy.
The human CD 19 molecule is a structurally distinct cell surface receptor expressed on the surface of human B cells, including, but not limited to, pre-B cells, B cells in early development {i.e., immature B cells), mature B cells through terminal differentiation into plasma cells, and malignant B cells. CD19 is expressed by most pre-B acute lymphoblastic leukemias (ALL), non-Hodgkin's lymphomas, B cell chronic lymphocytic leukemias (CLL), pro-lymphocytic leukemias, hairy cell leukemias, common acute lymphocytic leukemias, and some Null-acute lymphoblastic leukemias (Nadler et al, J. Immunol., 131:244-250 (1983), Loken et al, Blood, 70:1316-1324 (1987), Uckun et al, Blood, 71:13-29 (1988), Anderson et al, 1984. Blood, 63:1424-1433 (1984), Scheuermann, Leuk. Lymphoma, 18:385-397 (1995)). The expression of CD19 on plasma cells further suggests it may be expressed on differentiated B cell tumors such as multiple myeloma, plasmacytomas, Waldenstrom's tumors (Grossbard et al., Br. J. Haematol, 102:509-15 (1998); Treon et al, Semin. Oncol, 30:248-52 (2003)).
The CD 19 antigen has also been one of the many proposed targets for immunotherapy. The CLB-CD 19 antibody (anti-CD 19 murine IgG2a mAb) was shown to inhibit growth of human tumors implanted in athymic mice (Hooijberg et al, Cancer Research, 55:840-846 (1995)). In another study, the monoclonal murine antibody FMC63 (IgG2a) was chimerized using a human IgG1 Fc region (Zola et al, Immunol Cell Biol 69:411-22 (1991)). This antibody did not induce complement-mediated cytotoxicity or ADCC in vitro and administration to SCID mice bearing a human B cell lymphoma (xenotransplantation model) resulted in moderate but unspecified killing of the transplanted tumor cells (Pietersz et al, Cancer Immunol. Immunother., 41:53-60 (1995)).
The results obtained using xenotransplantation mouse models of tumor implantation led to studies using murine anti-CD 19 antibodies in human patients. The murine CLB-CD 19 antibody was administered to six patients diagnosed with a progressive non-Hodgkin's lymphoma who had failed previous conventional therapy (chemotherapy or radiotherapy). These patients were given total antibody doses ranging from 225 to 1,000 mg (Hekman et al, Cancer Immunol. Immunotherapy, 32:364-372 (1991)). Although circulating tumor cells were temporarily reduced in two patients after antibody infusion, only one patient achieved partial remission after two periods of antibody treatment. No conclusions regarding therapeutic efficacy could be drawn from this small group of refractory patients.
Subsequently, these investigators showed that the anti-tumor effects of unconjugated CD20 mAbs are far superior to those of CD 19 mAbs in transplantation models (Hooijberg et al, Cancer Res., 55:840-846 (1995); and Hooijberg et al, Cancer Res., 55:2627-2634 (1995)). Moreover, they did not observe additive or synergistic effects on tumor incidence when using CD 19 and CD20 mAbs in combination (Hooijberg et al, Cancer Res., 55:840-846 (1995)). Although the xenotransplantation animal models were recognized to be poor prognostic indicators for efficacy in human subjects, the negative results achieved in these animal studies discouraged interest in therapy with naked anti-CD 19 antibodies.
The use of anti-CD 19 antibody-based immunotoxins produced equally discouraging results. In early clinical trials, the B4 anti-CD 19 antibody (murine IgG1 mAb) was conjugated to the plant toxin ricin and administered to human patients having multiple myeloma who had failed previous conventional therapy (Grossbard et al., British Journal of Haematology, 102:509-515 (1998)), advanced non-Hodgkin's lymphoma (Grossbard et al, Clinical Cancer Research, 5:2392-2398 (1999)), and refractory B cell malignancies (Grossbard et al, Blood, 79:576-585 (1992)). These trials generally demonstrated the safety of administering the B4-ricin conjugate to humans; however, results were mixed and response rates were discouraging in comparison to clinical trials with RITUXAN™ (Grossbard et al, Clinical Cancer Research, 5:2392-2398 (1999)). In addition, a significant portion of the patients developed a human anti-mouse antibody (HAMA) response or a human anti-ricin antibody (HARA) response.
Given the fact that current therapies using naked anti-CD 19 antibodies or anti-CD 19 antibody-based immunotoxins produce equally discouraging results, there exists a need to develop anti-CD 19 antibodies that are more effective to treat CD19 mediated disorders, e.g. anti-CD 19 antibodies that are able to efficiently induce tumor cell death, by triggering apoptosis and blockade of B cell proliferation, and by mediating killing through ADCC.